Process for preparation of pyrazinoyland pyrazinamidoguanidines



United States Patent 3,506,662 PROCESS FOR PREPARATION OF PYRAZINOYL-AND PYRAZINAMIDOGUA'NIDINES Edward J. 'Cragoe, Jr., and John B. Bicking,Lansdale, Pa.,

assignors to Merck & Co., Inc., Rahway, N.J., a corporation of NewJersey No Drawing. Filed Apr. 30, 1968, Ser. No. 725,508 Int. Cl. C07d51/76 US. Cl. 260-250 10 Claims ABSTRACT OF THE DISCLOSURE A process isdescribed for the preparation of pyrazinoylguanidines andpyrazinamidoguanidines which comprises the reaction of a guanidine or anaminoguanidine with a 3,S-diamino-6-chloropyrazinethiolcarboxylateester. The products have utility as diuretic agents.

4 III wherein R represents (a) hydrogen,

(b) lower alkyl of from 1 to about 5 carbons, either straight orbranched chain, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,pentyl and the like,

(0) lower alkenyl of from 3 to about 5 carbon atoms,

e.g., allyl, Z-butenyl, and the like,

(d) lower(cycloalkyl-alkyl), wherein the lower cycloalkyl moiety hasfrom 3 to about 6 carbon atoms such as cyclopropyl, cyclopentyl, andcyclohexyl, and the lower alkyl moiety has from 1 to about 3 carbons,such as methyl, ethyl, and propyl;

R represents (a) lower alkyl of from 1 to about 5 carbon atoms such asmethyl, ethyl, propyl, butyl, and pentyl,

(b) mononuclear aryl, especially phenyl,

(c) mononuclear aryl-lower alkyl, especially phenyllower alkyl, whereinthe lower alkyl group has from 1 to about 3 carbon atoms such as methyl,ethyl and p py R represents (a) hydrogen,

(b) lower alkyl of from 1 to about 5 carbon atoms, such as methyl,ethyl, propyl, butyl, and pentyl, either straight or branched chain andeither unsubstituted or substituted with such as (1)hydroxy, (2)mononuclear aryl, especially phenyl;

3,506,662 Patented Apr. 14, 1970 ice R represents (a) hydrogen,

(b) lower alkyl of from 1 to about 5 carbon atoms, either straight orbranched chain, such as methyl, ethyl, propyl, butyl, and pentyl;

n is zero or one.

The products prepared by the process of this invention possess usefuldiuretic properties but more importantly they selectively enhance theexcretion of sodium and chloride ions while suppressing the excretion ofpotassium. They are especially useful in the treatment or management ofedema and other abnormalities resulting from the retention of excessquantities of sodium and/or fluid by the animal organism.

Prior to the invention of the present process the usual method ofpreparing these pyrazinoylguanidines and pyrazinamidoguanidinescomprised treating a normal ester, i.e., oxy-ester, of pyrazinoic acidwith a guanidine or an aminoguanidine. However, it was found that theesters often reacted very slowly and required drastic reactionconditions which increased the tendency toward side reactions such ascyclization of the product and other yield reducing effects. Hence, amore reactive derivative of the pyrazinoic acids was required. It wasfound that the thiolesters of the present invention are more reactivethan the corresponding oxy-esters toward guanidine and aminoguanidinethus permitting reaction at lower temperature for shorter times andcorrespondingly cleaner reaction mixtures and better yields.

The pyrazinethiolcarboxylate esters which form another embodiment ofthis invention, being useful novel compounds are prepared most readilyby either of two routes, designated herein as Method B and Method C.

METHOD B /N 1 /N RIHNT TNHQ (ROOM, RNT

wherein R and R have the meanings assigned above and R represents loweralkyl of from 1 to about 4 carbon atoms such as methyl, ethyl, propyl,or butyl, either straight or branched chain, and either unsubstituted orsubstituted with phenyl. The actual nature of R is not critical to thereaction as it does not appear in the resulting thiolester, but ratherit can arise from the use of any readily available organic acidanhydride. It has been found that butyric anhydride is very suitable andhas been used exclusively in the examples that follow, but as stated anycommon organic acid anhydride serves equally well.

The first step in the synthesis of the thiolesters, the preparation ofthe 2-R-6-chloro 7 acylamido-4H-pyrazino[2,3-d][1,3]oxazin-4-ones, V,com-prises heating the pyrazinoic acid (IV) in the acid anhydride offormula (RCO) O at reflux temperature or up to about C., if theparticular anhydride refluxes at a higher temperature, for from 1 toabout 3 hours. Upon cooling, Com- METHOD C R HNT TNH (3H3 Z w 01 \N/002E N 010 oPn-c-om 1v VII 2 COSR I VIII By this method thepyrazinethiolcarboxylates (I), are prepared by treating the pyrazinoicacid (IV) in a polar non-protic solvent such as dimethylformamidedimethyl sulfoxide dimethyl sulfone, acetonitrile, and tetrahydrofuranin the presence of a base such as a trialkylamine or pyridine withN-(t-butyl)-5-methylisoxazolium perchlorate (VII). Dilution of thereaction mixture with Water precipitates theN-(t-butyl)-3-(3,5-diamino-6-chloropyrazinecarbonyloxy)crotonamide(VIII). Treatment of VIII with a mercaptan, R SH in the presence of abase affords the pyrazinethiol esters (I).

The preparation of these novel thiol-esters by both methods is describedin the examples which follow from which the reaction conditions areapparent.

Having thus obtained the pyrazinethiol esters, the process of thisinvention, Method A, is conducted by preparation of a guanidine oraminoguanidine from the corresponding mineral acid addition salt andtreating the free base with the pyrazinethiolcarboxylate. The guanidineand aminoguanidine free base is normally obtained by treating a mineralacid addition salt with a solution of sodium in a lower alkanol such asmethanol, ethanol, propanol, isopropanol, or butanol and preferably byheating the mixture at reflux for 1 to 2 hours. Elevated temperaturesare not required but lower temperatures unnecessarily prolong reactiontimes. On evaporation of the alkanol solvent there is left a syrupyresidue which is treated directly with solid pyrazinethiocarboxylate (I)by warming for a few minutes at steam bath temperature or alternativelythe guanidine or aminoguanidine can be treated with a lower alkanolsolution of the pyrazinethiolcarboxylate. In either case gentle heatingpromotes the reaction but is not required. The product is isolated byevaporation of any solvent present, washing the residue with water andcollecting the solids on a filter.

The following examples described the preparations of the various 3,5diamino-6-chloropyrazinethiolcarboxylates and the process of thisinvention by the preparation of several pyrazinoylguanidines andpyrazinamidoguanidines. It is to be understood that the invention is notlimited to the specific compounds described in the examples or by thespecific reaction conditions described therein but is to be understoodto embrace variations and modifications thereof which fall Within thescope of the appended claims.

4 EXAMPLE 1 Butyl 3,S-diamino-6-chloropyrazinethiolcarboxylate STEP A:PREPARATION OF 2 PROPYL 6 CHLORO-7- BUTYRAMIDO 4H PYRAZINO[2,3(1][1,3]OXAZIN-4- ONE A mixture of 3,5 diamino-6-chloropyrazinoic acid(56.58 g., 0.30 mole) and butyric anhydride (500 ml.) is heated over aperiod of 30 minutes to C. and

the resulting solution is maintained at 150 C. for 1 hour longer.

The reaction solution is chilled in an ice bath and the resulting solidis collected by filtration and washed With ether. There is obtained 49.4g. (53%) of product, M.P. 163167 C. Recrystallization from butyricanhydride gives 40.1 g. (43%) of2-propyl-6-chloro-7-butyramido-4H-pyrazino [2,3-d] [1,3]oxazin-4-one,M.P. 172C.

Analysis.Calc. for C H ClN O (percent): C, 50.25; H, 4.87; N, 18.03.Found (percent): C, 50.13; H, 4.78; N, 18.21.

STEP B: PREPARATION OF BUTYL 3,5 BIS(BUTYR- AMIDO)-6-CHLOROPYRAZINETHIOLCARBOXYLATE A mixture of2-propy1-6-chloro-7-butyramido-4H-pyrazino[2,3-d][1,3]oxazin-4-one (3.1g., 0.01 mole), butyl mercaptan (2.7 g., 0.03 mole), triethylamine (100mg.) and ethyl acetate (25 ml.) is stirred at room temperature for 6hours until a clear solution is obtained. The solution is allowed tostand 16 hours while the crystalline product separates. The product iscollected and recrystallized from benzene to yield 2.2 g. (55%) of butyl3,5- bis(butyramido) 6 chloropyrazinethiolcarboxylate, M.P. 1235-1255 C.

Analysis.-Calc. for C17H25CIN4O3S (percent): C, 50.92; H, 6.29; N,13.97. Found (percent): C, 51.35; H, 6.05; N, 13.95.

Step 0: Preparation of butyl3,'5-diamino-G-chloropyrazinethiolcarboxylate A mixture of butyl3,S-bis(butyramido)-6-chloropyrazinethiolcarboxylate (3.0 g, 0.0075mole) 5% hydrochloric acid (20 ml.) and isopropyl alcohol (20 ml.) isheated 20 minutes on a steam bath until solution is complate. Thesolution is cooled, diluted with 20 ml. of water, and neutralized by theaddition of saturated sodium bicarbonate solution. The product whichprecipates is collected, and recrystallized from benzene to yield 1.0 g.(51%) of butyl 3,5-diamino-6-chloropyrazinethiolcarboxylate, M.P.129.5130.5 C.

Analysis.-Calc. for C H ClN OS (percent): C, 41.45; H, 5.02; N, 21.49.Found (percent): C, 41.12; H, 4.83; N, 21.37.

EXAMPLE 2 Phenyl 3,5-diamino-6-chloropyrazinethiolcarboxylate STEP A:PREPARATION OF PHENYL 3,5-BIS(BU TYR AMIDO)-6-CHLOROPYRAZINETHIOLCARBOXYLATE To a suspension of2-propy1-6-chloro-7-butyramid0- 4H-pyrazino[2,3-d][1,3]oxazin-4-one(from Example 1) (3.11 g., 0.01 mole) in ethyl acetate (25 ml.),containing triethylamine (200 mg), is added thiophenol (3.31 g., 0.03mole) and the resulting solution is stirred at room temperature for 1hour.

The reaction solution is concentrated to dryness under reduced pressureand the residue is recrystallized from cyclohexane. There is obtained3.50 g. (83%) of product, M.P. 137.5-l42 C. A second recrystallizationfrom cyclohexane gives 3.10 g. (74%) of 3,5-bis(butyramido)-6-chloropyrazinethiolcarboxylate, M.P. 142-144 C.

Analysis.--Calc. for C H ClN O S (percent): C, 54.22; H, 5.03; N, 13.31.Found (percent): C, 54.26; H, 5.08;'N, 13.39.

STEP B: PREPARATION OF PHENYL 3,5-DIAMINO-6-CHLOROPYRAZINETHIOLCARBOXYLATE A mixture of phenyl3,5-bis(butyramido)-6-chloropyrazinethiolcarboxylate (1.05 g., 0.0025mole), 5% aqueous hydrochloric acid (7 m1.) and isopropyl alcohol (7ml.) is heated on a steam bath with stirring for minutes.

The reaction mixture is cooled and the resulting solid is collected byfiltration, washed with water and dried. The yield is 0.67 g. (96%),M.P. 228-231 C. Recrystallization from acetonitrile gives 0.50 g. (72%)of phenyl 3,5 diamino 6 ch10ropyrazinethiolcarboxylate, M.P. 236-237 C.

Other esters of 3,S-diamino-6-chloropyrazinethiolcarboxylate prepared bythe process of Examples 1 and 2 are described in Table I. The productsare'prepared following substantially the same procedure described inExamples 1 and 2, except that the butylmercaptan of Example 1 and thephenylmercaptan of Example 2 is replaced by the appropriate mercaptan, RSH, defined inTable I.

I 81 .(n-C H CO)2O Cl. N COOH l N I N C3H7C ON -C3H1 @RZSH HN NH:

a Cl N Y Cl N GOSR TABLE I Example R R H CH3- H CzHa- 6 H n-CaH7 7 H0mn- 8 i-CaH7- CH3- 9 CH2= CH-CHr- C2H5 10 n-C4Hv- 11-03117- 12 IPClHr-EXAMPLE 13 Benzyl 3,5-diamino-6-chloropyrazinethiolcarboxylate STEP A:PREPARATION OF N (1: BUTYL) 3 (3,5DI-

AMINO-B-CHLOROPYRAZINECARBONYLOXY) CROTON- AMIDE STEP B: PREPARATION OFBENZYL 3,5-DIAMINO-6- CHLOROPYRAZINETHIOLCARBOXYLATE Sodium hydroxide(0.08 g., 0.002 mole) is dissolved in Water (0.5 ml.) followed by theaddition of acetonitrile (3.5 ml.). Benzyl mercaptan (0.15 ml.) isadded, stirred one minute and N-(t-butyl) 3(3,5-diamino-6-chloropyrazinecarbonyloxy)crotonamide (0.328 g., 0.001mole) is introduced. This reaction mixture is stirred for two hours anddiluted with water (6 ml.). The yellow solid that separates is collectedand dried, 0.25 g. M.P. 137-142 C. Recrystallization from acetonitrilegives benzyl 3,5 diamino 6 chloropyrazinethiolcarboxylate, M.P. -1465 C.

Analysis-Cale. for C H ClN OS (percent): C, 48.89; H, 3.76; N, 19.01.Found (percent): C, 48.98; H, 3.54; N, 18.85.

Other esters of 3,5-diamino-6-ch1oropyrazinethiolcarboxylate preparedbythe process'of Example 13 are described in Table 11. They are preparedfollowing substantially the same procedure described in Example 13,except that the benzyl mercaptan is replaced by the appropriatemercaptan, R SH, 'delned in Table II, and the3,S-diamino-6-chloropyrazinoic acid of Example 13 is replaced by theappropriate 3-amino-5-NHR -6-chloro- I pyrazinoic acid.

I N HN NHz o1 COOH solid is washed with water. Purification isaccomplished TABLE II by dlssolvmg the product in aqueous mehanesulfonlcacid, Eampm filtering and reprecipitating with aqueous sodium solution.

CH3- There is obtained 0.90 g. (77%) of 3,5-diamino-6-chloro- 3 52i}; 5pyrazinoylguanidine, M.P. 240.5241.5 C. (dec.). n-C4Hr- Analysis.-Calc.for C H ClN O (percent): C, 31.38;

H, 3.51; N, 42.70. Found (percent): C, 31.15; H, 3.54;

Quatern- N, 42.54.

3,5-diamino-6-chloropyrazinoylguanidine is similarly 19 H G 10 preparedemploying the procedure of Example 25, but

substituting for the butyl 3,5-diamino-o-chloropyrazinethiolcarboxylateutilized therein an equivalent amount of 82%; any one of thecorresponding methyl, ethyl, propyl, phenn-caHiethyl, phenyl, or benzylesters, described in Examples 2 to 7, and 14 to 19. n-C Hy Alsoemploying the procedure of Example 25, but substituting for the butyl3,5-diamino-6-chloropyrazinethiolcarboxylate and the guanidinehydrochloride used there- 24 1PC4H9- in, equivalent amounts of theesters of 3-amino-5-NHR 6-chloropyrazinethiolcarboxylate and a guanidineof EXAMPLE 25 formula 3,5-diamino-6-chloropyrazinoylguanidine To asolution of sodium (0.58 g., 0.025 mole) in isopropyl alcohol (20 ml.)is added guanidine hydrochloride 25 (2.63 g., 0.0275 mole) and theresulting suspension is heated under reflux for minutes with stirring.The re- NH 4 action mixture is concentrated to a paste under reducedpressure and the residue is treated with butyl 3,5-diamino-6-chloro-pyrazinethiolcarboxylate (1.30 g., 0.005 mole). 30

The mixture is heated on a steam bath for 5 minutes. described in TableIII there are produced the 1-(3-amino- After cooling to roomtemperature, the reaction mixture 5 NHR -6-chloropyrazinoyl)-3-R -3-R-guanidines also is stirred with water (10 ml.), filtered and thecollected depicted in Table III.

IIIIH /R' N H2NCN\ N R HN-l/ NH: R R'HN NH:

C1 COSR Cl CONH-CN NH R TABLE III Starting material from Ex. Example R RB. R M.P. 0.) end of product 26 4, 15 H C2H5- H 252-254.

27 2, 19 H Q CHa- CH:- 277 (HCLHzO).

28 5, 16 H n-CaHr- OH2CH2OH H 228.5229.5(HC1).

CHg- CH (CH2) 2- (CH2) 31 8, 20 1-CaH1 CH3- CH H 300. 32 8,20 1-CaH7CHa- CHr- CHa- 238. 5-240. 33 8, 20 i-CaH1 CHa- CHzCH2OH H 185-186(HC1.l/2H2O).

34 8, 20 1-CaH7 (3113- H 200.5-204. 5.

35- 9,21 CH3CH=CH: C3H5 H H 213-214. 36 9, 21 CHr-CH=CH2 C2Hs- CHa- CHa213-215. 37 10, 22 n-C4H9' n-CaHr- CH3- 011 187. 5.

38 11, 23 I1-C4Ht H H 220-221. 5.

39 12, 24 n-CrHo- Q CH; CH; 187. 5.

3,5 -diamino-6-chloropyrazinamidoguanidine hydrochloride described inTable IV, there are produced the l-(3-aminowherein R is a memberselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, and C cycloalkyl-lower alkyl;

R is a member selected from the group consisting of lower alkyl, phenyl,and phenyl-lower alkyl;

R is a member selected from the group consisting of hydrogen, loweralkyl, hydroxy-lower alkyl, and phenyllower alkyl;

R is a member selected from the group consisting of hydrogen, and loweralkyl; and

n is an integer selected from 0 and 1.

2. A process as claimed in claim 1 wherein R and R are hydrogen, and nis 0.

3. A process as claimed in claim 1, wherein R and R are hydrogen, and nis 1.

4. A process as claimed in claim 1, for the preparation of the compoundof formula N HzNir o1 C-NH 5 NHR-6-chloropyraz1nam1do)-3-R -3-R-guan1d1ne also H 2 described 'in Table IV. NH

N NH N R HN NH2 A RIHN NH:

2 01 \N oosn 01 \\N/ CONHNH E N TABLE IV Starting material M.P. C.) ofExample iromexample R1 R2 R3 R4 end product 41 4,15 H C2H5- (311 H252-253(HC1).

42 2,19 H Q- CH3- CH3 279-280(HC1).

43 a, 14 H CH3 (cH2)20H H 243-244 H01 44 4,15 H GZHF- -0H H 242-245 Ho145 5,16 H 11-0311? amp-Q H 248-249 (H01).

46 6,13 H CHz- OH3 H 252-253(1101).

47 7,18 H Q-wmn- CH3- CH 279-280 (H01).

48 9, 21 CH2CH=CH2 021%- H H 1s2F1sa(Hc1 What is claimed is: 55 1. Aprocess for the preparation of a compound of structural formula 5. Aprocess as claimed in claim 1, for the preparation of the compound offormula I IH 6. A compound of structural formula N RHNI TNHZ 01 --o-sRwherein R is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, and C -cycloalky1-lower alkyl; and

1 1 1 2 R is selected from the group consisting of lower alkyl,References Cited Phenyl and UNITED STATES PATENTS 7. The compound asclaimed in clalm 6, whereln R 1s hydmgm 3,432,502 3/1969 Pollak et a1.260-250 8. Butyl 3,S-diamino--chloropyrazinethiolcarboxylate.

9. Phenyl 3,5 diamino-6-ch1oropyrazinethio1carb0X- ylate.

10. Benzyl 3,5 diamino-6-ch10ropyrazinethiolcarboxylate. 424-250 5NICHOLAS S. RIZZO, Primary Examiner

